Patient-Matched Stem Cells of the Barrett's-Dysplasia-Adenocarcinoma Sequence

在癌症生物学中缺乏可靠的、针对患者的模型一直是阻碍 了解异质性、进展、转移和化疗耐药性。的最新进展 克隆驻留在正常再生上皮中的成体干细胞的技术已经适应于 从巴雷特的食道克隆干细胞。拟建中心的调查人员现在延长了这一期限 在初步研究中，克隆发育不良的巴雷特氏症和腺癌本身的干细胞的技术。 这项技术对解决巴雷特氏症和癌症生物学中的关键问题的影响包括 从前驱病变、功能和基因组肿瘤内发生肿瘤的确切步骤 异质性及其对化疗耐药性的影响，最后是干细胞的性质和靶向性 前驱病变和直立性腺癌，具有潜在的变革性。因为潜在的变革性是 利用这些干细胞的再生和克隆性质来扩展我们对 以并行方式处理不同的案例。在目标1中，我们将生成干细胞克隆的高密度阵列 对应于对早期腺癌患者的四个黏膜切除进行的拓扑抽样。 AIM 2将从晚期食管腺癌病例中产生大型癌症干细胞库。 AIM 3将生成一个交互数据库，该数据库链接来自以下两个克隆阵列的数据集 粘膜切除以及与癌症干细胞文库分析相关的切除。我们期待着 这样一个数据集的虚拟数据库将极大地增加下游研究的相同库和 离散克隆，因为每个克隆都带有这样的链接数据集，这些数据集将通过正在进行的和 中心内部和整个社区的调查人员未来的研究。

The absence of reliable, patient-specific models in cancer biology has been a chronic impediment to understanding heterogeneity, progression, metastasis, and chemotherapy resistance. Recent advances in technologies for cloning adult stem cells resident in normal, regenerative epithelia have been adapted to cloning stem cells from Barrett's esophagus. Investigators in the proposed Center have now extended this technology, in preliminary studies, to cloning the stem cells of dysplastic Barrett's and adenocarcinoma itself. The impact of this technology for resolving key questions in Barrett's and cancer biology in general, including the precise steps in tumorigenesis from precursor lesions, the functional and genomic intra-tumor heterogeneity and its impact on chemotherapy resistance, and lastly the nature and targetability of stem cells of precursor lesions and frank adenocarcinoma, is potentially transformative. As potentially transformative is a biorepository that exploits the regenerative and clonal nature of these stem cells to extend our knowledge of discrete cases in parallel fashion. In Aim 1, we will generate high-density arrays of stem cell clones corresponding to a topological sampling across four mucosal resections of patients with early adenocarcinoma. Aim 2 will generate large libraries of cancer stem cells from advanced cases of esophageal adenocarcinoma. Aim 3 will generate an interactive database that links datasets from both the arrays of clones derived from mucosal resections as well as those associated with analyses of the cancer stem cell libraries. We anticipate that such a virtual database of datasets would greatly augment downstream studies with the same libraries and discrete clones as each would come with such linked datasets that would be further extended by ongoing and future studies by investigators within the Center and across the community.